Motor Complications and Treatment in Advanced Parkinson's Disease #456

Background

Motor symptoms of idiopathic Parkinson's Disease (PD) include bradykinesia (slowness of movement), tremor, muscle rigidity, gait impairment, and falls. Many individuals develop these symptoms within 10 to 20 years of PD onset (see Fast Fact #361 for PD trajectory and Fast Facts #362 for management of nonmotor symptoms). In advanced PD, the risk–benefit balance of PD medications often shifts, necessitating treatment modifications. This Fast Fact provides a primer for the generalist clinician regarding the management of motor symptoms in patients with advanced PD, including at the end of life.

Signs and Symptoms of Advanced PD

• Worsening gait and falls: Falls increase as PD progresses and can be catastrophic. Risk factors include freezing of gait, impaired balance, loss of postural control, orthostasis, and impulsivity.^1,2 These factors may indicate the need for more robust nonpharmacological management (see next section).

• Motor fluctuations: When motor symptoms are well controlled on PD medications (specifically dopaminergic medications), this is referred to as the on state. The off state or “end-of-dose failure” describes how symptoms worsen as dopaminergic agents wear off. Up to 96% of patients with advanced PD experience off states.³ As PD progresses, patients spend less of their overall time in the on state. Furthermore, on/off motor fluctuations often are abrupt and worsen quality of life.^2,4–7 Even while on, patients with advanced PD may be highly disabled and dependent on caregivers.⁴

Nonpharmacological Management

Exercise, especially gait training that uses audio or visual cues to overcome freezing of gait, is beneficial to mitigate functional decline.¹ Costly equipment such as weighted walkers and sit-to-stand lifts, if needed, should be obtained before hospice enrollment since hospice agencies frequently cannot cover their costs. Physical therapy is paramount in enhancing movement and mitigating motor progression of PD, even in nonambulatory patients. However, physical, occupational, and speech therapies are often capitated in hospice settings. In such situations, one can consider paying out of pocket for a physical therapist, physical therapy student, or personal trainer who is familiar with PD.⁸ Web-based exercise routines specific to PD are also available (see Ref.⁹).

Pharmacological Management

The mainstay of pharmacological treatment for PD is typically levodopa, which is a precursor of dopamine and aims to reduce muscle rigidity and other PD-related motor symptoms. Levodopa is often combined with carbidopa (Sinemet^®) in one pill to prevent the premature conversion of dopamine in the bloodstream. Beyond Sinemet though, patients with PD often require an array of other medications, such as amantadine, dopamine agonists (e.g., ropinirole and pramipexole), catechol-O-methyltransferase (COMT) inhibitors (e.g., entacapone), monoamine oxidase b (MAO-b) inhibitors (e.g., selegiline and rasagiline), and occasionally, anticholinergics (e.g., trihexyphenidyl). As PD advances into the final phases, levodopa remains the most effective motor treatment and the one least likely to worsen hallucinations, impulsivity, and orthostatic hypotension. Thus, often adjuvant medications are gradually and sequentially discontinued by the treating neurologist, yielding carbidopa/levodopa (CD/LD) monotherapy.

Withdrawal Syndromes

Ideally, the deprescribing process of adjuvant PD medications should occur by the patient's treating neurologist before hospice enrollment since hospice enrollment can be a barrier for the necessary specialist-level monitoring. However, this may not be achievable, hence clinicians should be aware of the two most significant withdrawal syndromes in PD motor management:

• Rapid discontinuation of dopamine agonists can cause Dopamine Agonist Withdrawal Syndrome, which manifests as anxiety, pain, nausea/vomiting, and drug cravings.

• Discontinuation of large doses of CD/LD can cause uncomfortable and potentially life-threatening complications such as muscle rigidity, neuroleptic malignant syndrome, and rhabdomyolysis.

Levodopa Management at End of Life

Because CD/LD monotherapy can provide symptomatic benefit by palliating rigidity and anxiety in the last weeks of life, it should not be discontinued merely because a patient is on a comfort-focused plan of care. However, clinicians should be alert for levodopa-related side effects in advanced PD such as exacerbation of visual hallucinations^10,11 and orthostasis.¹² These side effects may occur due to a narrowing therapeutic window as patients grow seriously ill and can adversely affect quality of life, mood, functional status, and caregiving needs.^7,13–15 Although dyskinesias (abnormal involuntary movements) may be most noticeable to observers, they are the least likely side effect to bother the patient and need not be addressed unless causing falls or injuries.^3,4,6 If significant side effects from levodopa are noted, clinicians (including hospice providers) should reach out to the treating neurologist for guidance. When patients lose the ability to safely swallow medications, the following considerations may help:

• Most CD/LD tablets can be crushed and dissolved in orange juice.

• Contents of extended-release CD/LD capsules can be sprinkled in one to two tablespoons of applesauce.

• Orally disintegrating tablets of levodopa are readily available (Parcopa^®); inhalation powders and intestinal suspensions are also available but far more expensive, with higher side effect profiles.

• Insertion of a nasogastric (NG) tube is generally avoided due to the associated discomfort; however, clinicians should be aware that sometimes the discomfort from rigidity can be so severe that patients may prefer NG tube placement to facilitate levodopa administration.

Additional Pharmacological Considerations at End of Life

Common dopamine receptor blocking agents used to treat agitation and nausea (e.g., haloperidol, olanzapine, and metoclopramide) should be avoided as they can irreversibly worsen motor symptoms. Quetiapine (in low doses) is the preferred anti-dopamine treatment if a medication in this class is necessary for necessary. Ondansetron is the antiemetic of choice. Hospice programs should consider developing PD-specific comfort kits.

Summary

Considering the complexities involved in PD medication management, ideally, the neurologist should be part of the hospice plan of care. At a minimum, the neurologist and the generalist/hospice clinician should connect at the time of hospice enrollment and when considering PD medication changes.